As researchers continue to collect evidence supporting new uses for angiotensin-converting enzyme (ACE) inhibitors, experts are urging physicians to use the drugs to treat more—and different kinds of—patients.

For years, ACE inhibitors have been the drug of choice to treat congestive heart failure. Overwhelming evidence has shown that the drugs improve symptoms and mortality rates, and help boost exercise levels in these patients. ACE inhibitors are also often used to control blood pressure.

But researchers are increasingly finding that ACE inhibitors can do much more. Besides preventing heart attacks and strokes, studies have shown that the drugs can prevent or delay decline in kidney function and the complications—or even the onset—of diabetes.

Perhaps even more surprisingly, ACE inhibitors' effectiveness often transcends their ability to lower blood pressure. Researchers are discovering that ACE inhibitors can hinder inflammation, encourage the sprouting of new blood vessels, stem fibrosis and prevent remodeling of the heart after a myocardial infarction.

While most physicians know ACE inhibitors prevent heart attacks, the drugs also hinder inflammation and encourage new blood vessels.

And if those benefits aren't enough to make you a believer, ACE inhibitors are well-tolerated, often producing nothing more than a persistent cough. While some physicians may worry that the drugs will cause their patients' creatinine levels to rise, experts say that a spike in creatinine does not indicate kidney damage—and should not keep physicians from prescribing ACE inhibitors.

Now that several clinical trials have produced evidence supporting ACE inhibitors, clinical guidelines are endorsing the drugs for a variety of uses. "ACE inhibitors are coming of age," noted Domenic A. Sica, FACP, a nephrologist with the Medical College of Virginia in Richmond.

Here's a look at how the experts—and recent practice guidelines—suggest using ACE inhibitors to treat or prevent common diseases.

Hypertension and cardiac protection

Physicians can currently choose from 10 different ACE inhibitors on the market. While there are significant differences among them, all lower blood pressure about as effectively as diuretics and beta-blockers. (See "Are all ACE inhibitors the same?") For that reason, the World Health Organization/International Society of Hypertension recommends ACE inhibitors as first-line therapy for patients with high blood pressure.

While the National Heart, Lung, and Blood Institute's expert committee on high blood pressure opted not to give ACE inhibitors the same rank as diuretics and beta-blockers, timing is largely to blame. When the committee put out its report in 1997, clinical trials hadn't yet shown the drugs to be as effective at lowering mortality.

Because new data have come to light since the report was issued, an update from the institute would likely elevate ACE inhibitors to a first-line therapy, according to Donald G. Vidt, FACP, a nephrologist with the Cleveland Clinic Foundation and a member of the institute's expert committee.

While preventing high blood pressure is a proven way to help prevent heart attacks, coronary heart disease and congestive heart failure, researchers have been surprised by ACE inhibitors' ability to do more than merely lower blood pressure.

The large Heart Outcomes Prevention Evaluation (HOPE) study, for example, found that the average drop in blood pressure in patients at high risk for a cardiovascular event could not fully explain the remarkable 22% drop in incidence of heart attacks, cardiovascular death and stroke in subjects taking the ACE inhibitor ramipril. Even in patients with normal blood pressure, researchers found that ramipril prevented or caused a regression of left ventricle enlargement. (Other studies found similar results.)

Researchers say that the extra protection that ACE inhibitors give patients is not a statistical fluke, but likely comes from the drugs' impact on inflammation, plaque formation and other processes that would otherwise lead to heart disease. (For more information, see "How do ACE inhibitors work?")

Regardless of the mechanism, the HOPE study results were so encouraging that the 2001 American Heart Association/American College of Cardiology guidelines urged physicians to consider using ACE inhibitors to treat all patients with coronary or other vascular disease.

More recently, the FDA approved ramipril therapy to prevent heart attacks and other cardiovascular events in high-risk patients. The green light from the FDA applies to even those patients who don't have high blood pressure.

The FDA's decision was bolstered by another study that found ACE inhibitors may stave off atherosclerosis. An offshoot of the HOPE trial, that study found that during a one-year period, ramipril reduced narrowing of the carotid artery by half.

Post-MI treatment

Not only do ACE inhibitors appear to prevent heart attacks, but they can boost the survival rates—by up to 20%—of patients who have recently had a heart attack and also suffer from congestive heart failure. The drugs can also cut by nearly one-third the likelihood that patients will develop congestive heart failure after having a heart attack.

As a result, the American Heart Association and the American College of Cardiology both recommend using ACE inhibitors to treat heart attack patients. Most experts recommend starting ACE inhibitor therapy within a day of having a heart attack, as long as low blood pressure isn't a problem. Patients then typically continue treatment for the rest of their lives.

Besides ACE inhibitors, statins, aspirin and beta-blockers all have also been shown to help prevent cardiovascular disease events or boost survival odds after a heart attack. While many experts suggest juggling these medicines simultaneously, patient compliance often suffers.

"Every time we add another medicine, we know compliance goes down," said Darryl K. Potyk, FACP, a general internist in Spokane, Wash. "If we try to be too zealous, we're going to have patients getting into too many problems with polypharmacy." (Dr. Potyk added that he also worries that patients might substitute a preventive medicine for a treatment medicine.)

But as James B. Young, MD, a cardiologist with the Cleveland Clinic Foundation, pointed out, "There are all sorts of tricks to help with compliance. Have patients take their aspirin and beta-blocker in the morning, then take their ACE inhibitor and statin at bedtime. They need to get in the habit of setting their pill bottles in the right spot."

Stroke

When it comes to preventing strokes in high-risk patients, the evidence is not entirely clear. While the HOPE study found that ramipril slashed the incidence of stroke by as much as one-third, another large study on hypertensive patients found captopril increased the risk of stroke compared to conventional therapy with diuretic, beta-blockers or both. Most experts, however, discount the results of the captopril research because of a flawed study design.

Further confusing the issue is the large study that goes by the acronym PROGRESS. In 2001, researchers reported that when they combined the ACE inhibitor perindopril with a diuretic, they cut the stroke risk nearly in half for both hypertensive and normotensive patients who had suffered a stroke within the last five years. Perindopril used alone, however, made no dent in stroke risk.

Based on the HOPE study, the 2001 American Heart Association guidelines to prevent stroke recommend ramipril for high-risk patients and for patients with diabetes and hypertension. While some physicians say they don't necessarily use ACE inhibitors to prevent stroke, they often wind up using them to control patients' blood pressure.

"I haven't used ACE inhibitors as a preferred drug to prevent recurrent stroke," said Dr. Vidt from Cleveland Clinic, "but I'm going to control blood pressure for these patients with whatever it takes. That usually requires two, three or four drugs," one of which is often an ACE inhibitor.

Diabetes

Probably the biggest surprise to come out of research on ACE inhibitors was the HOPE investigators' finding that ramipril appeared to prevent diabetes. During the four-and-a-half-year study, researchers found one-third fewer new cases of diabetes among patients over 55 who had vascular disease and took ramipril. Those results have been confirmed by one smaller study.

As more researchers try to replicate those results, some physicians have already started to treat patients at high risk of developing diabetes with ACE inhibitors. General internist Melvyn L. Sterling, FACP, Governor for the Southern California Region II Chapter, for example, said he considers prescribing ACE inhibitors to significantly overweight patients with a strong family history of type 2 diabetes.

Others such as Dr. Sica, however, said they haven't yet been swayed by the data on diabetes prevention. He said he plans to hold off using ACE inhibitors for that purpose until he sees more supportive data.

Once patients have diabetes, however, most studies seem to suggest that ACE inhibitors can help in several ways:

The drugs cut in half the incidence of cardiovascular events and produce modest reductions in blood pressure.

ACE inhibitors lower the risk of developing or experiencing a progression of kidney disease by one-quarter, a degree not attainable by other hypertensive drugs—except for angiotensin receptor blockers. (See "When should you consider ARBs?")

The drugs slow the progression of retinopathy in patients with normal blood pressure levels.

The American Diabetes Association recommends ACE inhibitors for diabetics with microalbuminuria. The organization also recommends the drugs for diabetics over 55 with hypertension, and for diabetics who don't have hypertension but have another risk factor for cardiovascular disease. It is a rare diabetes patient who doesn't meet one of these criteria.

Kidney disease

In patients without diabetes, researchers have consistently found that ACE inhibitors slow the progression of kidney disease.

One large study found that benazepril cut in half the number of patients who needed dialysis or whose serum creatinines doubled during a three-year period. Even in patients who had normal blood pressure but protein in their urine, ACE inhibitors significantly slowed the progression to end-stage renal disease.

Many doctors steer away from using ACE inhibitors for patients with signs of kidney disease because these drugs often prompt a rise in serum creatinine. They view significant spikes in creatinine as a red flag that a drug might be inflicting or worsening kidney damage.

Because the overall benefits of ACE inhibitors are so overwhelming, experts say that withholding treatment to avoid boosting creatinine levels is short-sighted.

Experts are quick to point out, however, that a rise in creatinine does not necessarily mean kidney damage. There are physiological reasons why ACE inhibitors prompt a rise in creatinine that have nothing to do with kidney damage, pointed out Dr. Sica. This rise is usually only temporary and will often stabilize or decline within a few months of starting ACE inhibitors. (Studies show that the greater patients' creatinine levels are before starting ACE inhibitor therapy, the more benefits they will reap for their kidneys from the therapy.)

Because the overall benefits of ACE inhibitors are so overwhelming, Dr. Sica said that withholding treatment to avoid boosting creatinine levels is short-sighted. That perspective is also reflected in American Heart Association guidelines for ACE inhibitor therapy, which Dr. Sica coauthored.

ACE inhibitors aren't for everyone with kidney disease. Experts say that you should hold off giving them to your patients with renal artery stenosis. And to avoid serious side effects from ACE inhibitors, you need to regularly monitor your patients' potassium and electrolyte levels.

ACE inhibitor as first choice?

Despite the growing interest in ACE inhibitors, doctors have other less expensive drug options for treating hypertension. So when should ACE inhibitors be your first choice?

Most experts recommend treating mild hypertension with diuretics because the drugs are cheap and pose few side effects. An ACE inhibitor is warranted if patients also have diabetes, are at high risk for cardiovascular disease, have congestive heart failure or show signs of kidney disease.

Some doctors such as Dr. Vidt said they would be inclined to prescribe an ACE inhibitor to patients with mild high blood pressure and a strong family history of diabetes. "We're now in a position where we can individualize therapy based on patients' comorbidities," he noted.

Dr. Sica said that because beta-blockers also prevent migraines and can help treat panic disorder and other anxiety-related problems, he chooses beta-blockers over ACE inhibitors for patients with those conditions as well as high blood pressure.

Dr. Young, however, said he typically chooses ACE inhibitors over beta- or calcium-channel blockers because he is so impressed with their anti-atherosclerotic benefits. These benefits have not been seen with other blood pressure drugs, he pointed out, with the possible exception of angiotensin receptor blockers.

But as Dr. Vidt noted, "Often the issue of what drug is better becomes a moot point. You start them on a diuretic and wind up putting them on an ACE inhibitor, beta-blocker and a calcium-channel blocker down the road. That's often what it takes to control their blood pressure."

Dr. Sica added, "Some patients need to take ACE inhibitors because there aren't cheaper alternatives that provide the same protection. The data are too compelling."

Margie Patlak is a freelance science writer in Elkins Park, Pa.

The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of ACP-ASIM.

Although all angiotensin-converting enzyme (ACE) inhibitors have the same basic mechanism of action, do they work the same in patients? No one knows for sure.

All ACE inhibitors have been shown to be equally effective at lowering blood pressure, but only about half have been tested for treating heart failure, and only a few have been studied in renal disease patients. Whether the dose used to get a specific response to one ACE inhibitor will be equivalent to that of another ACE inhibitor or for another indication is also an unanswered question.

If you want to be a purist, prescribe only those ACE inhibitors that have proven effective for the conditions you hope to ameliorate and at the doses used in clinical studies, suggested Donald G. Vidt, FACP, a nephrologist with the Cleveland Clinic Foundation in Ohio. You should also keep in mind that many HMOs will pay for only the ACE inhibitors they list on their formulary.

That said, here are the drugs and doses used in clinical studies for various indications:

ACE inhibitors were first developed to treat high blood pressure. By the 1970s, research revealed that the renin-angiotensin system played a key role in hypertension by generating angiotensin II, a powerful constrictor of blood vessels.

While researchers were studying how the venom of the Brazilian pit viper causes a severe and often fatal drop in blood pressure, they serendipitously discovered that the venom contains a compound that inhibits the angiotensin-converting enzyme (ACE) that makes angiotensin II from angiotensin I. Tinkering with this compound led to the first synthetic ACE inhibitor, captopril, which hit the market in 1981.

When it comes to countering high blood pressure, ACE inhibitors provide a one-two punch. They not only inhibit production of a blood vessel constrictor, but they also protect blood vessel dilators, such as bradykinin, from being digested by angiotensin-converting enzymes. Bradykinin, in turn, promotes the production of nitric oxide, which is thought to dilate blood vessels and hinder blood clotting and atherosclerosis.

Angiotensin II also appears to foster a number of processes that underlie cardiovascular disease, including inflammation, plaque formation, fibrosis and excessive growth of arterial walls and the left ventricle. Animal and clinical studies suggest that ACE inhibitors hinder many of these damaging processes. ACE inhibitors also may benefit people with cardiovascular disease by encouraging new blood vessels to sprout. One ACE inhibitor, quinapril, was recently shown to do this in animal studies.

By lessening inflammation and fibrosis, ACE inhibitors are thought to stall the progress of kidney disease. ACE inhibitors can also boost blood flow to the pancreas, reduce insulin clearance from the liver and hamper inflammation. All these feats might help explain why these drugs appear to delay or prevent the development of diabetes or its complications.

"It is amazing that one class of drugs can have so many effects in the body," noted cardiologist James B. Young, a cardiologist with the Cleveland Clinic Foundation in Ohio. "It would be too good to be true if just one clinical study showed this, but a multitude of clinical studies are repeatedly demonstrating benefits."

When the first angiotensin II-receptor blockers (ARBs) hit the market in the last decade, they generated a fair amount of confusion. Their cousins, the angiotensin-converting enzyme (ACE) inhibitors, had already proven effective for treating several conditions, so many doctors were left wondering why they should switch to ARBs.

Researchers expected angiotensin II-receptor blockers to fare better than ACE inhibitors because they are designed to specifically block angiotensin II effect. In practice, however, the new drugs haven't lived up to that expectation.

Researchers also worried that patients who took ARBs rather than ACE inhibitors would likely lose many of the benefits of ACE inhibitors, which help preserve bradykinin. But studies suggest ARBs also boost levels of these blood vessel dilators, although by a different mechanism.

While ARBs have not outperformed ACE inhibitors, research has suggested that the drugs equal ACE inhibitors when it comes to lowering blood pressure, stalling kidney disease progression, preventing heart attacks and strokes, and relieving symptoms and improving the longevity of patients with congestive heart failure. One large study of the ARB losartan found that this drug, like ramipril and captopril, appears to prevent or delay the onset of diabetes.

ARBs do have a clear advantage over ACE inhibitors when it comes to side effects. While ACE inhibitors produce few side effects, ARBs cause virtually none. Because ARBs cost more than ACE inhibitors, however, most doctors prescribe ARBs to only those patients who can't tolerate ACE inhibitors.

The bigger issue is whether to give patients combination therapy with both an ACE inhibitor and an ARB. In theory, such a combination would work better than either drug alone by more completely blocking angiotensin II.

Clinical data exploring the safety and effectiveness of ARB/ACE inhibitor combos are just starting to trickle in. While results are preliminary, they seem to suggest that combination therapy may be a better alternative for some patients. Here's what some of these studies have found:

For heart failure patients, the combined drugs produced greater reduction in blood pressure and more effectively boosted exercise capacity, reduced hospitalizations and prevented cardiac remodeling than either drug alone.

For patients with kidney disease and normal blood pressure, the drug combination more effectively reduced protein in the urine than either drug alone.

The combination was well-tolerated.

But definitive findings from large, well-designed studies of ACE inhibitor/ARB combinations have yet to surface. For now, some doctors such as Donald G. Vidt, FACP, a nephrologist with the Cleveland Clinic Foundation, give both drugs to congestive heart failure patients who don't respond sufficiently to either drug alone.

Darryl K. Potyk, FACP, a general internist in Spokane, Wash., has tried this strategy on occasion, but he is waiting for better evidence that the combo is effective before putting more of his patients on it.

"We've been misled by too many early studies, and it's unfair to patients," he said. "I don't want to end up blowing with the breeze and giving them whatever is in vogue at the time."

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